title: Induction of high mobility group box 1 release from serotonin-stimulated human umbilical vein endothelial cells.
abstract: High mobility group box 1 (HMGB1) is a non-histone nuclear protein which is released from the nucleus of activated macrophages into the extracellular space in response to stimuli such as endotoxin or necrosis. The HMGB1 functions as a potent proinflammatory cytokine in the extracellular spaces. Recently, HMGB1 has been implicated in the progression of atherosclerosis. However, the association between HMGB1 and the development of atherosclerosis is poorly understood. Therefore, we examined whether serotonin (5-HT), a key factor involved in the development of atherosclerosis, induced HMGB1 release in human umbilical vein endothelial cells (HUVECs). We found that 5-HT induced the release of HMGB1 but not of ERK1/2 and JNK from HUVECs via the 5-HT receptor (5-HT1B)/p38 mitogen-activated protein kinase (MAPK) signaling pathway. The p38MAPK inhibitor SB203580 and the 5-HT1B antagonist GR55526 markedly inhibited HMGB1 release from 5-HT-stimulated HUVECs. The vascular endothelial growth factor (VEGF) derived from activated macrophages in atherosclerotic lesions also plays an important role in the progression of atherosclerosis. We found that HMGB1 induced VEGF production in macrophage-like RAW264.7 cells. HMGB1 induced the activation of p38MAPK, ERK1/2 and Akt. The PI3-kinase inhibitor LY294002 significantly inhibited VEGF production in HMGB1-stimulated macrophages, while other kinase inhibitors did not. These results suggest that HMGB1 release may contribute as a risk factor in the development and progression of atherosclerosis.
authors.affiliation: Department of Laboratory and Vascular Medicine, Cardiovascular and Respiratory Disorders, Advanced Therapeutics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890-8520, Japan.
authors.forename: Ko-Ichi
authors.initials: K
authors.lastname: Kawahara
authors.forename: Teruto
authors.initials: T
authors.lastname: Hashiguchi
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Kikuchi
authors.forename: Salunya
authors.initials: S
authors.lastname: Tancharoen
authors.forename: Naoki
authors.initials: N
authors.lastname: Miura
authors.forename: Takashi
authors.initials: T
authors.lastname: Ito
authors.forename: Yoko
authors.initials: Y
authors.lastname: Oyama
authors.forename: Yuko
authors.initials: Y
authors.lastname: Nawa
authors.forename: Kamal K
authors.initials: KK
authors.lastname: Biswas
authors.forename: Xiaojie
authors.initials: X
authors.lastname: Meng
authors.forename: Yoko
authors.initials: Y
authors.lastname: Morimoto
authors.forename: Binita
authors.initials: B
authors.lastname: Shrestha
authors.forename: Hisayo
authors.initials: H
authors.lastname: Sameshima
authors.forename: Ikuro
authors.initials: I
authors.lastname: Maruyama
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000378:metabolism* / Q000473:pathology; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism / Q000473:pathology; D002867:Chromones / Q000494:pharmacology; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D024243:HMGB1 Protein / Q000378:metabolism*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D048670:MAP Kinase Kinase 4 / Q000037:antagonists & inhibitors / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D011725:Pyridines / Q000494:pharmacology; D044302:Receptor, Serotonin, 5-HT1B / Q000378:metabolism; D012701:Serotonin / Q000494:pharmacology*; D058825:Serotonin 5-HT1 Receptor Agonists; D018490:Serotonin Agents / Q000494:pharmacology*; D014471:Umbilical Veins / Q000378:metabolism* / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D002867:Chromones; D004791:Enzyme Inhibitors; D024243:HMGB1 Protein; D007093:Imidazoles; D048670:MAP Kinase Kinase 4; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D011725:Pyridines; D044302:Receptor, Serotonin, 5-HT1B; D012701:Serotonin; D058825:Serotonin 5-HT1 Receptor Agonists; D018490:Serotonin Agents; D042461:Vascular Endothelial Growth Factor A; D048051:p38 Mitogen-Activated Protein Kinases; C467484:VEGFA protein, human; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C093642:SB 203580